CN118697770A - Use of Lactobacillus paracasei 207-27 in regulating mood - Google Patents

Abstract

The present application relates to the use of Lactobacillus paracasei or its progeny, or a composition comprising the Lactobacillus paracasei or its progeny in the preparation of a medicine. The Lactobacillus paracasei or its progeny, or a composition comprising the same, has outstanding efficacy in improving anxiety, depression and sleep.

Description

Use of Lactobacillus paracasei 207-27 in regulating mood

Technical Field

The present application relates to the use of Lactobacillus paracasei or its progeny, or a composition comprising the Lactobacillus paracasei or its progeny in the preparation of a medicine. The Lactobacillus paracasei or its progeny, or a composition comprising the same, has outstanding efficacy in improving anxiety, depression and sleep.

Background Art

In today's society, people are under increasing pressure from work and life due to the dual effects of the environment and social competition. Their mental and spiritual health levels are generally in a sub-healthy state. The number of patients with insomnia, anxiety and depression is on the rise, which seriously affects their daily work and life and has become a disease that cannot be ignored. The symptoms and signs of anxiety include restlessness or tension, a sense of imminent danger, panic or doom; increased heart rate, rapid breathing, sweating, tremors, feeling weak or tired; difficulty sleeping or having gastrointestinal diseases, etc. Anxiety often accompanies depression. Depression is characterized by continuous and long-term low mood as its main clinical feature. The two symptoms often penetrate each other, so the treatment methods are similar.

At present, the treatment of anxiety and depression mainly includes psychotherapy and clinical antidepressants. Clinical antidepressants include selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. These drugs include escitalopram, duloxetine and paroxetine. In addition, an anti-anxiety drug called buspirone can be used continuously. Certain sedatives such as benzodiazepines can also relieve anxiety symptoms, but they are generally only used for short-term relief of acute anxiety. Although these drugs have certain efficacy in the treatment of anxiety and depression, it generally takes nearly two weeks to take effect, and most maintenance treatments require stability for at least three months. The adverse reactions and side effects caused during the treatment are large. Moreover, these drug therapies with high treatment costs and strong side effects are not suitable for patients with mild symptoms and sensitive patients. Therefore, it is necessary to develop products with small side effects and dependence, suitable for a wide range of people with mild anxiety and depression, or for the prevention of anxiety and depression.

Scientific research in recent years has found that the prevalence of mental illnesses such as depression, anxiety and stress is increasing. It is particularly important to control the symptoms as early as possible to prevent them from developing into serious diseases.

However, the products (especially probiotics) that can relieve anxiety and depression and improve negative emotions in the prior art are relatively limited. Therefore, the development of new probiotics and their compositions that can improve sleep, relieve anxiety and other negative emotions has great scientific significance and application prospects.

Summary of the invention

The patent applicant screened a probiotic strain, Lactobacillus paracasei 207-27, in the early stage, and its microbial preservation number is: GDMCC No.60960. In the subsequent research process, it was unexpectedly found that the strain has outstanding effects in improving anxiety, depression and sleep. For example, it can improve depression and anxiety (for example, improve the curiosity of mammals to the external environment under the disease model), and also has the ability to affect the synthesis of neurotransmitters (for example, 5-HT, GABA, DA, NE, GLU), or the factors of stress hormones and hypothalamus-pituitary-adrenal axis (for example, cortisol).

Therefore, in a first aspect, the present application provides a use of Lacticaseibacillus paracasei or its progeny, or a composition comprising the Lacticaseibacillus paracasei or its progeny in the preparation of a medicament or food, wherein the medicament or food is used to prevent and/or treat mood disorders in a subject, or to prevent and/or treat diseases or symptoms caused by mood disorders;

The Lactobacillus paracasei is deposited in Guangdong Microbiological Culture Collection Center with the deposit number of GDMCC No.60960.

In therapeutic applications, the Lactobacillus paracasei of the present application will be used in an amount that can treat (for example, suppress) the symptoms of a disease and/or its complication to a certain extent. The amount that satisfies the above-mentioned is defined as "therapeutically effective amount" in this article. The above-mentioned therapeutically effective amount will depend on many factors well known to those skilled in the art, for example, the severity of the disease, or the patient's body weight and the general condition.

In the prevention application, the Lactobacillus paracasei of the present application will be administered to a patient who is susceptible to a specific disease or is at risk of a specific disease in an amount that can reduce the risk of the disease to a certain extent. Such an amount is defined as a "prevention effective amount". Equally, the specific prevention effective amount depends on many factors specific to the patient, for example, the patient's health status and body weight.

Therefore, in certain embodiments, the Lactobacillus paracasei or its progeny of the present application, or the Lactobacillus paracasei or its progeny contained in a composition or medicament, will be administered to a subject in a preventive and/or therapeutically effective amount.

If at least a portion of the lactobacillus paracasei of the application exists in a living form, consider that these bacterium can colonize and breed in the intestine, it is all effective to use the lactobacillus paracasei of any concentration in theory.In certain embodiments, at least a portion of the lactobacillus paracasei of the application exists in the form of viable bacteria in the composition or medicine that comprise it.In certain preferred embodiments, at least a portion of the lactobacillus paracasei of the application is alive when arriving intestinal tract. Like this they can be retained in the intestine, and can improve effectiveness by propagation.In certain preferred embodiments, the lactobacillus paracasei of the application also can be by interacting with symbiotic bacteria and/or host to bring into play an effect.

Mood disorders (e.g., depression, anxiety) can have adverse effects on a person's health, i.e., can affect and/or change a person's thinking, feelings, and/or behavior (or all three). In some embodiments, a person suffering from a mood disorder (e.g., depression, anxiety) may have varying degrees of psychological and/or physical problems in social, work, or family activities. Diseases caused by mood disorders (e.g., depression, anxiety) can change a person's thinking, feelings, and/or behavior in the same or different ways.

Mood disorders

In certain embodiments, mood disorders include depression and anxiety.

In certain embodiments, the disease and/or symptoms caused by a mood disorder (eg, depression) are selected from depression, bipolar disorder, seasonal affective disorder, dysthymia, depressive personality disorder, altered mental status, or any combination thereof.

In certain embodiments, the depression is selected from major depressive disorder, atypical depression, typical or melancholic depression, psychotic depression, catatonic depression, antenatal and/or postnatal depression, double depression, recurrent brief depression, minor depression, or any combination thereof.

As used herein, the term "anxiety" refers to a specific psychological state involving extreme fear or worry. When anxiety reaches a certain level, it can lead to different diseases, including but not limited to panic attacks, panic disorder, agoraphobia, social phobia or social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (ASD), generalized anxiety disorder and acute stress disorder. In particular, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are closely related to anxiety.

In certain embodiments, the disease and/or symptoms caused by a mood disorder (e.g., anxiety) are selected from panic attack, panic disorder, agoraphobia, social phobia or social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (ASD), generalized anxiety disorder, acute stress disorder, or any combination thereof.

Depression and anxiety are interactive, and a person may not only suffer from a disease and/or symptom caused by depression and/or anxiety. Therefore, in certain embodiments, the subject is in depression and anxiety at the same time. In certain embodiments, the subject is in anxiety first and then depression. In certain embodiments, the subject is in depression first and then anxiety. The symptoms of depression and anxiety are divided into early and late stages. In the early stage, you may be in a state of sensitivity, tension, and depression in individual time periods, but you can still carry out daily activities. In this case, it may cause slight memory loss, sleep disorders, etc. In the later stage, you may be in a state of sensitivity, tension, and depression for a long time, which may lead to the loss of the ability to handle work/life normally for part of the time. In severe cases, the above symptoms may further transform into a disease (e.g., major depressive disorder) and produce suicidal thoughts.

Sleep disorders

Mood disorders and sleep disorders may interact, and a person may not suffer from just one disorder. Therefore, in certain embodiments, the subject suffers from both a mood disorder and a sleep disorder. In certain embodiments, the subject suffers from a mood disorder first and then a sleep disorder. In certain embodiments, the subject suffers from a sleep disorder first and then a mood disorder.

In certain embodiments, symptoms caused and/or resulting from a mood disorder include: sleep disturbances (e.g., sleep apnea, narcolepsy, insomnia, parasomnias, sleep deprivation), feeling sad or depressed, confusion or decreased concentration, memory loss, excessive fear or worry, extreme guilt, extreme mood swings, withdrawal from friends and activities, detachment from reality, paranoia or hallucinations, inability to cope with daily problems, stress, difficulty understanding situations and people, difficulty relating to situations and people, significant changes in eating habits, changes in sexual desire, excessive anger, hostility or violence, thoughts of suicide, or any combination thereof.

Therefore, in certain embodiments, the above symptoms can be used to determine whether the subject suffers from a mood disorder.

In certain embodiments, the Lactobacillus paracasei or its progeny contained in the medicament or composition prevents and/or treats a mood disorder in a subject by affecting the synthesis of neurotransmitters (e.g., 5-HT, GABA, DA, NE, GLU) in the subject, or by affecting stress hormones and factors of the hypothalamus-pituitary-adrenal axis (e.g., Cortisol) in the subject.

In certain embodiments, the Lactobacillus paracasei or its progeny contained in the medicament or composition prevents and/or treats a mood disorder in a subject by affecting the subject's stress response (e.g., increasing the level of serotonin (5-HT), dopamine (DA), norepinephrine (NE), γ-aminobutyric acid (GABA) and/or glutamate (Glu), and/or reducing the level of cortisol (CORT)).

drug

As used herein, the term "pharmaceutical" encompasses pharmaceuticals for use in humans as well as pharmaceuticals for use in animals (ie, veterinary applications). In certain embodiments, the pharmaceutical is for use in humans.

In certain embodiments, the drug is used alone or in combination with other antifungal agents, analgesics, anti-inflammatory drugs, healing agents, or moisturizers.

In certain embodiments, the medicament further comprises an additional active ingredient.

In certain embodiments, the additional active ingredient is an additional drug; preferably, the additional drug is selected from anxiolytics, sedatives, hypnotics, antipsychotics, antidepressants, anticonvulsants, opioid analgesics, or any combination thereof.

In certain embodiments, the additional active ingredient is a dietary supplement.

In certain embodiments, the dietary supplement is selected from melatonin, an omega-3 dietary supplement, or any combination thereof.

In certain embodiments, the medicament comprises a preparation of Lactobacillus paracasei.

In certain embodiments, the drug further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include a cryoprotectant such as glycerol, or a cryoprotectant selected from sugars such as sucrose, fructose, trehalose; sugar alcohols such as glycerol, sorbitol, mannitol; polysaccharides such as cellulose, starch, gum, maltodextrin; polyethers such as polypropylene glycol, polyethylene glycol, polybutylene glycol; antioxidants such as natural antioxidants such as ascorbic acid, β-carotene, vitamin E, glutathione, chemical antioxidants; oils such as rapeseed oil, sunflower oil, olive oil; surfactants such as Tw een20, Tween80, fatty acids, etc.; peptones, such as soy peptone, wheat peptone, whey peptone; tryptophan, vitamins, minerals such as iron, manganese, zinc; hydrolysates, such as protein hydrolysates, such as whey powder, malt extract, soybeans; amino acids, peptides, proteins, nucleic acids, nucleotides, nucleobases such as cytosine, guanine, adenine, thymine, uracil, xanthine, hypoxanthine, inosine; yeast extract; beef extract; growth factors; lipids; and combinations thereof.

The medicine comprising Lactobacillus paracasei or its composition of the present application can be applied to the experimenter with any clinically allowed application form and therapeutically effective amount. In an exemplary embodiment, the medicine is applied to the experimenter by oral, sublingual, nasal, intrathecal, bronchial, rectal, percutaneous, inhalation or parenteral administration.

The drug of the present invention can be formulated in the form of solid, semisolid, liquid or gas into pills, powders, capsules, tablets (eg, effervescent tablets), film-coated tablets, orally dissolving granules, liquids, suppositories or enemas.

Pharmaceutical forms suitable for oral administration are selected from the group including but not limited to drops, syrups, decoctions, elixirs, suspensions, extemporaneous suspensions, drinkable vials, tablets, capsules, granules, cachets, pills, tablets, lozenges, lozenges or freeze-dried forms.

In a more specific embodiment, the medicament comprising Lactobacillus paracasei or a composition thereof of the present application is presented and/or orally administered in a form suitable for oral administration. The form suitable for oral administration is selected from the list including but not limited to drops, syrups, decoctions, elixirs, suspensions, extemporaneous suspensions, drinkable vials, tablets, capsules, granules, cachets, pills, caplets, lozenges, lozenges or freeze-dried forms.

In certain embodiments, the drug or food is a drug targeted for gastrointestinal release, or a drug controlled for release in the gastrointestinal tract.

In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is selected from mice, pigs, rabbits, monkeys, sheep, and humans.

In certain embodiments, the Lactobacillus paracasei is administered to the subject in an amount of 10 ⁶ to 10 ¹² CFU/daily dose.

In certain embodiments, the Lactobacillus paracasei is administered to the subject in an amount of 10 ⁶ CFU/day dose, 10 ⁷ CFU/day dose, 10 ⁸ CFU/day dose, 10 ⁹ CFU/day dose, 10 ¹⁰ CFU/day dose, 10 ¹¹ CFU/day dose, or 10 ¹² CFU/day dose.

In certain embodiments, the Lactobacillus paracasei is present in the medicament in an amount of 10 ⁶ to 10 ¹² CFU/dose.

In certain embodiments, the Lactobacillus paracasei is present in the medicament in an amount of 10 ⁶ CFU/dose, 10 ⁷ CFU/dose, 10 ⁸ CFU/dose, 10 ⁹ CFU/dose, 10 ¹⁰ CFU/dose, 10 ¹¹ CFU/dose, or 10 ¹² CFU/dose.

Composition

In this document, the term "composition" has a broad meaning, that is, the composition may contain a single microbial component (e.g., a strain of Lactobacillus paracasei and other components (e.g., nutrients), or may contain multiple microbial components (e.g., a strain of Lactobacillus paracasei and other microbial strains.

In certain embodiments, the composition comprises the Lactobacillus paracasei or progeny thereof, and another bacterium and/or fungus (eg, yeast), wherein the other bacterium and/or fungus is a probiotic or is edible.

In certain embodiments, the probiotic is selected from Bifidobacterium, Lactobacillus, Lactobacillus casei, Lactobacillus mucosus, Lactobacillus plantarum, Lactobacillus unisomeris, Lactobacillus spp., Streptococcus, Lactococcus, Propionibacterium, Propionibacterium, Leuconostoc, Pediococcus, Weizmannella, Zoococcus, Staphylococcus, or any combination thereof.

In certain embodiments, the yeast is of the genus Kluyveromyces.

In certain embodiments, the composition further comprises additional additives.

In certain embodiments, the additional additive is a nutrient selected from dietary fiber, prebiotics, protein, lipids, minerals, vitamins, plant extracts, or any combination thereof.

In certain embodiments, the Bifidobacterium is selected from Bifidobacterium adolescentis, Bifidobacterium animalis subsp. animalis, Bifidobacterium animalis subsp. lactis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, Bifidobacterium longum subsp. longum, or any combination thereof.

In certain embodiments, the Lactobacillus genus is selected from: Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacilus kefiranofaciens subsp. Kefiranofaciens, or any combination thereof.

In certain embodiments, the Lactobacillus species is selected from the group consisting of Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, or any combination thereof.

In certain embodiments, the Lactobacillus species is selected from the group consisting of: Limosilactobacillus fermentum, Limosilactobacillus reuteri, or a combination thereof.

In certain embodiments, the Lactobacillus is Lactobacillus plantarum.

In certain embodiments, the Lactobacillus salivarius is Ligilactobacillus salivarius.

In certain embodiments, the Streptococcus is Streptococcus salivarius subsp. thermophilus.

In certain embodiments, the Propionibacterium spp. is Propionibacterium freudenreichii subsp. shermanii.

In certain embodiments, the Propionibacterium is Propionibacterium acidipropionici.

In certain embodiments, the Lactococcus spp. is selected from the group consisting of: Lactococcus lactis subsp. Lactis, Lactococcus lactis subsp. Lactisbiovar diacetylactis, Lactococcus cermoris, or any combination thereof.

In certain embodiments, the compositions may be used to prepare food products.

In the text, the term "food" is used in a broad sense, including food and drink for humans, and also covers food and drink (ie feed) for animals. In certain embodiments, the food is suitable for and designed for human consumption.

It is to be understood that, depending on the purpose, application mode or administration mode, the food of the present application may be in the form of liquid, solid, suspension or powder.

In certain embodiments, the food is selected from solid beverages, candies or juices, or the food is a dairy product (eg, yogurt, flavored fermented milk, lactic acid bacteria beverage, cheese).

In certain embodiments, the food product is a dietary supplement or a nutraceutical.

As used herein, the term "dietary supplement" refers to an edible product that can provide a beneficial effect (eg, a nutritional effect, a preventive effect, a therapeutic effect, or other beneficial effect) to a consumer.

As used herein, the term "health food" refers to food that claims to have specific health functions or is intended to supplement vitamins and minerals. Health food is a special food, not a medicine. Health food can be in various forms such as tea, wine, bee products, drinks, soups, fresh juices, and medicinal foods.

In certain embodiments, the dietary supplement or nutraceutical is formulated for oral administration.

In certain embodiments, the food may also include (but not limited to) one or any combination of the following substances: probiotics (e.g., probiotic bacteria), carbohydrates (e.g., dietary fiber), proteins (e.g., enzymes), lipids (e.g., fats), vitamins, and minerals.

In certain embodiments, the food product may also include an immunomodulator.

In certain embodiments, the food may further include plant ingredients (eg, flavonoids, polyphenolic plant extracts, etc.), milk substitutes, or metabolites or extracts of Bifidobacterium breve or its progeny.

In certain embodiments, the strain of the present invention can also be combined with various sweeteners or flavoring agents, coloring substances, stabilizers, glidants, fillers and other excipients acceptable in food.

In certain embodiments, the food product further comprises a prebiotic.

In certain embodiments, the prebiotic is selected from fructooligosaccharides, galacto-oligosaccharides, xylo-oligosaccharides, isomaltooligosaccharides, soy oligosaccharides, inulin, spirulina, arthrospira, versicolor polysaccharide, carrot nitrogen-containing polysaccharide, casein hydrolyzate, α-lactalbumin, lactoferrin, or any combination thereof.

In certain embodiments, the food is in the form of a pill, a powder, a capsule, a tablet (eg, an effervescent tablet), a film-coated tablet, an orally disintegrating granule, or a liquid.

The patent applicant has screened a probiotic bacterium-Lactobacillus paracasei 207-27 in the early stage, and its microbial preservation number is: GDMCC No.60960. The inventor of the present application has confirmed through a large number of experiments that this Lactobacillus paracasei has good tolerance to gastric acidic environment and bile salts, and has good adhesion to intestinal tract, has the effect of improving immunity. In subsequent research, it has been found that this bacterial strain has significant effect in improving anxiety and depression symptoms, regulating bad mood, and has completed the present invention thus.

Therefore, on the other hand, the present application provides a use of Lacticaseibacillus paracasei or its progeny, or a composition comprising the Lacticaseibacillus paracasei or its progeny in the preparation of a medicine or food, wherein the medicine or food is used to improve anxiety and depression symptoms and alleviate negative emotions in a subject, or prevent negative emotions such as anxiety caused by factors such as stress.

Among them, the Lactobacillus paracasei was preserved in the Guangdong Provincial Microbiological Culture Collection Center on January 15, 2020, and the preservation number was GDMCC No.60960.

Another object of the present application is to provide the use of Lactobacillus paracasei 207 27 as a probiotic in relieving anxiety and improving negative emotions such as depression.

The Lactobacillus paracasei 207-27 of the present application has good tolerance to gastric acid and bile salts, and meets the basic requirements of probiotics.

Definition of terms

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, the molecular genetics, nucleic acid chemistry, chemistry, molecular biology, biochemistry, cell culture, microbiology, cell biology, genomics and recombinant DNA procedures used herein are conventional procedures widely used in the corresponding fields. At the same time, in order to better understand the present invention, the definitions and explanations of the relevant terms are provided below.

As used herein, the term "paracasei lactobacillus (Lacticaseibacillus paracasei)" and "paracasei lactobacillus (Lactobacillus paracasei)" refer to identical bacterial strains, and can be used interchangeably.Wherein, paracasei lactobacillus is the updated strain name, and paracasei lactobacillus is the former strain name, and the specific source can be found in "List of strains that can be used for food".The name of its genus has also been updated to "Lactobacillus (Lactobacillus)" by "Lactobacillus (Lactobacillus)".

As used herein, the term "treat" refers to counteracting the effects or symptoms caused by a disease or pathological condition in a subject (e.g., a mammal, e.g., a human), including: (i) inhibiting the disease or pathological condition, i.e., slowing its development; (ii) alleviating the disease or pathological condition, i.e., causing regression of the disease or pathological condition or its symptoms; (iii) stabilizing the disease or pathological condition.

As used herein, the term "prevent" refers to preventing the occurrence of a disease, i.e., preventing the development of a disease or pathological condition in a subject (e.g., a mammal, e.g., a human), particularly when the subject is at risk for the pathological condition.

As used herein, the term "probiotic" refers to a microorganism or its cell component that has a beneficial effect on the health or well-being of the host. Microorganisms that can be used as probiotics are well known in the art, for example, see Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999: 10107-10 (Salminen S. Ouwehand A. Benno Y. et al. "How to define probiotics"); and "Trends in Food Science and Technology", 1999, No. 10, pp. 107-110. In certain embodiments, probiotics may include a single strain of microorganisms. In certain embodiments, probiotics may include a mixture of multiple strains and/or a mixture of multiple bacterial species and genera. In the case of a probiotic composition, "probiotics" may also be used to refer to a probiotic composition or preparation. For the purposes of the present invention, a microorganism of the genus Lactobacillus paracasei is considered to be a probiotic.

As used herein, the term "prebiotic" refers to a substance that can promote the growth or amplification of at least one probiotic strain. In certain embodiments, a prebiotic can promote the growth or amplification of at least one probiotic strain in a subject (e.g., in the human gastrointestinal tract). In certain preferred embodiments, the prebiotic can promote the growth or amplification of Lactobacillus paracasei in the human gastrointestinal tract.

As used herein, the term "offspring" refers to the daughter cells produced by microorganisms by growth (e.g., culture growth in culture medium). It is understandable that, in the culture process of microorganisms, genetic material may change (e.g., mutation of 1 or several bases, displacement or deletion), and different strains have significant distinctions in the presence or absence of the same function (see, e.g., IPAinternational probiotics association). Therefore, in certain embodiments, the offspring has the same function (e.g., can improve immunity, improve allergic reactions, etc.) compared with the strain derived from it. In certain embodiments, the offspring has the same physiological and biochemical characteristics (e.g., colony morphology is the same, with the same 16s DNA) compared with the strain derived from it, and has the same function (e.g., can improve depression and anxiety (e.g., promote the degree of curiosity of mammals to the external environment under the disease model)). In certain embodiments, the offspring of the Lactobacillus paracasei is a gram-positive bacteria, and the colony morphology is rod-shaped or rod-shaped, with sharp edges and corners, without spores.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is pharmacologically and/or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to, pH regulators, surfactants, adjuvants, and ionic strength enhancers. For example, pH regulators include, but are not limited to, phosphate buffers; surfactants include, but are not limited to, cationic, anionic or nonionic surfactants, such as Tween-80; ionic strength enhancers include, but are not limited to, sodium chloride.

As used herein, the term "dietary supplement" refers to an edible product that can provide a beneficial effect (eg, a nutritional effect, a preventive effect, a therapeutic effect, or other beneficial effect) to a consumer.

As used herein, the term "food" includes food and drink for humans, and also encompasses food and drink (ie, feed) for animals. In certain embodiments, the food product is suitable for and designed for human consumption.

As used herein, the term "drug" encompasses drugs for use by both humans and animals in human and veterinary medicine, as well as drugs for incorporation into animal feed (e.g., livestock feed and/or pet food). In addition, the term "drug" as used herein means any substance that provides a therapeutic, preventive, and/or beneficial effect.

As used herein, the term "CFU (Colony-Forming Units)" refers to the total number of microorganisms such as bacteria, fungi, yeast, etc. in a product, and is usually used for calculation of viable bacteria count.

As used herein, the term "daily dose" refers to the amount taken in one day (24 hours) with a dose or respectively with several doses. As used herein, the term "CFU/daily dose" means the amount of bacteria present in the composition/food/medicine provided to the subject ^{every day. For example, in certain embodiments, Lactobacillus paracasei exists (for example 10 8 to} 10 ¹² CFU/daily dose) in the food/medicine. In this embodiment, if Lactobacillus paracasei is applied to food/medicine (for example, in solid beverage, yogurt), the food/medicine (for example solid beverage, yogurt) provided to the subject every day can contain about ^{10 6} to 10 ¹² Lactobacillus paracasei of CFU. Of course, alternatively, this amount of bacteria can be divided into multiple administrations, as long as the total amount of Lactobacillus paracasei received by the subject in any particular time (e.g., during each 24-hour period) is from about 10 ⁶ to about 10 ¹² CFU of the bacteria, i.e., the above-mentioned Lactobacillus paracasei is present in the food in an amount of 10 ⁶ to 10 ¹² CFU/day dose (e.g., 10 ⁸ to 10 ¹² CFU/day dose).

Advantageous Effects of the Invention

The patent applicant screened a probiotic strain, Lactobacillus paracasei 207-27, in the early stage, and its microbial preservation number is: GDMCC No.60960. In the subsequent research process, it was unexpectedly found that the strain has outstanding efficacy in improving anxiety, depression and sleep. For example, it can improve depression and anxiety (for example, improve the curiosity of mammals to the external environment under the disease model), and also has the ability to affect the synthesis of neurotransmitters (for example, 5-HT, GABA, DA, NE, GLU), or affect the factors of stress hormones and hypothalamus-pituitary-adrenal axis (for example, cortisol). At the same time, it has been found in the previous study that the strain has good tolerance to gastric acid and bile salts. Therefore, the strain has a higher potential in improving the anxiety symptoms of the subject and relieving depression, or preventing the anxiety and other bad emotions caused by factors such as pressure.

Embodiments of the present invention will be described in detail below in conjunction with examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention, rather than to limit the scope of the present invention. According to the following detailed description of preferred embodiments, various objects and advantages of the present invention will become apparent to those skilled in the art.

DETAILED DESCRIPTION

The invention will now be described with reference to the following examples which are intended to illustrate the invention rather than to limit the invention.

Unless otherwise specified, the experiments and methods described in the embodiments are carried out substantially according to conventional methods well known in the art and described in various references. For example, conventional techniques such as immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA used in the present invention can be found in Sambrook, Fritsch and Maniatis, MOLECULAR CLONING: A LABORATORY MANUAL, 2nd edition (1989); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (ed. by F.M. Ausubel et al., (1987)); METHODS IN ENZYMOLOGY series (Academic Publishing Company): PCR 2: A PRACTICAL METHOD. APPROACH) (M. J. MacPherson, B. D. Hames, and G. R. Taylor, eds. (1995)), and ANIMAL CELL CULTURE (R. I. Freshney, ed. (1987)).

In addition, if the specific conditions are not specified in the examples, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified in the reagents or instruments used, they are all conventional products that can be obtained commercially. It is known to those skilled in the art that the embodiments describe the present invention by way of example and are not intended to limit the scope of the present invention. All public cases and other references mentioned herein are incorporated herein by reference in their entirety.

Example 1. Study on the effect of Lactobacillus paracasei 207-27 on improving anxiety and depression in rats

The patent applicant screened a probiotic bacterium-Lactobacillus paracasei 207-27 in the early stage, and applied for a patent (Lactobacillus paracasei 207-27 (Lactobacillus paracasei 207-27) has been preserved in the Guangdong Microbial Culture Collection Center (GDMCC, Guangdong MicrobialCulture Collection Center) on the 5th floor of Building 59, No. 100, Xianlie Middle Road, Guangzhou City, with a preservation number of GDMCC No.60960, and the preservation time is January 15, 2020). In the subsequent research process, it was unexpectedly found that Lactobacillus paracasei 207-27 has outstanding effect in improving anxiety and depression. Therefore, the present embodiment selects another 3 strains of bacteria (all Lactobacillus paracasei) in the same strain library as a comparison, and experiments are carried out together with Lactobacillus paracasei 207-27 of the present application (these strains all show relatively good acid and bile resistance and good cell adhesion in the early probiotic property research).

All Lactobacillus paracasei involved in this application are derived from By-Health's own strain library, and all strains in the strain library are isolated from normal full-term newborn fecal samples born in the West China Women's and Children's Hospital of Sichuan University. Among them, the inclusion criteria for newborns are: living in the five urban districts of Chengdu; gestational age 37-42 weeks, birth weight between 2500-4000g, and infants without congenital abnormalities or birth defects. Exclusion criteria are: mothers have used antibiotics within one month before delivery; parents have infectious diseases such as AIDS, tuberculosis, hepatitis B, etc.; newborns cannot collect feces due to serious diseases such as neonatal pneumonia.

Fresh feces of infants within 1-4 months after birth were collected in sterile fecal collection tubes. After sampling, they were immediately stored at 4°C and sent to the laboratory by the sampling personnel at low temperature for dilution culture. If the operation could not be performed immediately, they were stored anaerobically at 4°C and cultured on the same day. Subsequently, they were isolated and purified by the plate method to obtain single strains. The specific species of the isolated strains were identified by Mérieux API 50CH and 16SrDNA sequencing, and they were numbered (207-27, 207-28, 207-30, 207-31) and preserved in By-Health's own strain library.

1.1 Experimental methods

1.1.1 Experimental strains

All Lactobacillus paracasei involved in this experiment originated from By-Health's own strain library, which was isolated from fecal samples of normal full-term newborns born in the West China Women's and Children's Hospital of Sichuan University.

1.1.2 Animal model construction

Experimental animals: 80 SPF male SD rats, weighing 220-240 g. Provided by Beijing Huafukang Biotechnology Co., Ltd., experimental production license number: SCXK (Beijing) 2019-0008; use license number: SYXK (Tianjin) -2021-0003.

Modeling method: The chronic unpredictable mild stress (CUMS) model is an animal model that simulates the disease state of patients with depression. It is often used in the screening of antidepressant drugs and experimental studies on the pathophysiological mechanisms of depression. The specific methods are: fasting or water deprivation for 24 hours/time; swimming in 4℃ ice water for 5-8 minutes/time; wet bedding for 8 hours/time; restraint in a restraint cage for 2 hours/time; clamp the tail with a dovetail clip for 2 minutes/time; 60Hz noise stimulation for 1 hour/time; day and night reversal for 24 hours. Two stimuli were randomly given every morning and not repeated within 3 days.

1.1.3 Experimental Animal Grouping

The male rats were randomly divided into 8 groups, with 10 rats in each group.

(1) Blank control group (Control): no stress stimulation, intragastric administration of 1 ml of normal saline per day;

(2) Model group (CUMS): given stress stimulation, intragastric administration of 1 ml of normal saline per day;

(3) Lactobacillus paracasei 207-27 intervention group (CUMS-207-27): given stress stimulation, intragastric administration of 1 ml/day, the amount of probiotics was 10 ⁹ CFU/day;

(4) Lactobacillus paracasei 207-28 intervention group (CUMS-W21): given stress stimulation, intragastric administration of 1 ml/day, and the amount of probiotics was 10 ⁹ CFU/day;

(5) Lactobacillus paracasei 207-30 intervention group (CUMS-LD3): given stress stimulation, intragastric administration of 1 ml/day, and the amount of probiotics was 10 ⁹ CFU/day;

(6) Lactobacillus paracasei 207-31 intervention group (CUMS-207-31): given stress stimulation, intragastric administration of 1 ml/day, the amount of probiotics was 10 ⁹ CFU/day;

(7) Positive drug 1-methyltryptophan control group (CUMS-1-MT): given stress stimulation, gavage 10 mg/kg/day; purchased from Tianjin Jimi Biotechnology Co., Ltd. 1-Methyltryptophan is an orally active indoleamine 2,3-dioxygenase (IDO) pathway inhibitor, and IDO can catalyze the degradation of tryptophan to kynurenine.

(8) Positive drug fluoxetine control group (CUMS-Flu): Stress stimulation was given, 10 mg/kg/day by gavage; fluoxetine was purchased from Tianjin Jime Biotechnology Co., Ltd. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) type antidepressant, which is widely used in clinical practice.

Except for the rats in the blank control group, the rats in the other groups were subjected to chronic unpredictable mild stimulation for 6 weeks to establish a rat depression and anxiety model. Corresponding intervention measures were given from the 7th to the 11th week, during which chronic stimulation continued. After the intervention, behavioral tests were performed to evaluate the depression and anxiety levels of the rats in each group.

1.1.4 Behavioral indicator testing

① Open field test: The experimental device is a box with a size of 625mm (L) × 740mm (W) × 510mm (H) and the bottom is completely painted black. The experiment is carried out in a quiet environment. The rat is carefully placed in the center of the bottom of the box, and the camera system is used to observe and record the activity of the rat within 5 minutes. The observation indicators include horizontal movement-movement distance; vertical movement-number of standing times: the number of times the forelimbs leave the horizontal ground by more than 1 cm. After each test, clean the experimental box with 75% ethanol solution to remove the smell, urine and feces of the previous rat. The activity in the central area is negatively correlated with depression and anxiety, and the activity in the peripheral area is positively correlated with depression and anxiety.

② Elevated plus maze: At the beginning of the experiment, the rats were placed in the maze from the central grid to the closed arm, and their activities were recorded within 5 minutes. The observation indicators include: the number of entries into the open arm (two front paws must enter the arm), the time spent in the open arm, the number of entries into the closed arm, and the time spent in the closed arm. The proportion of time spent in the open arm, the proportion of the number of entries into the open arm, and the total number of entries into the elevated plus maze were calculated. After the experiment, the rats were taken out, the two arms were cleaned, and alcohol was sprayed to remove the odor. Finally, the data were analyzed using animal behavior software. The number of times the rats entered the open arm and the time they stayed there were negatively correlated with the depression and anxiety of the rats. The fewer times they entered the open arm and the shorter the time they stayed there, the more severe the depression and anxiety of the rats.

③Sugar water preference experiment: Before the experiment, the rats were adapted to sugar water for 24 hours, and they were deprived of water and food for 24 hours after the experiment. During the formal experiment, each rat was given 2 bottles of water in advance: 1 bottle of 2% sucrose water and 1 bottle of tap water. The experiment was ended after 1 hour, and the sucrose water consumption and pure water consumption of each rat were calculated. The sugar water preference index was calculated according to the formula % = sugar water consumption/(sugar water consumption + pure water consumption) × 100%. The sugar water preference index was negatively correlated with the depression and anxiety of rats. The lower the sugar water preference index, the more severe the depression and anxiety of the rats.

1.1.5 Biochemical index detection

① Puncture the ventral side of the aorta, collect blood samples and centrifuge to collect the upper serum. Enzyme-linked immune-sorbent assay (ELISA) was used to measure the levels of 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), and corticosterone (CORT).

② The whole brain tissue homogenate of rats was obtained, and the contents of 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), γ-aminobutyric acid (GABA), and glutamate (Glu) were detected by ELISA.

1.2 Experimental Results

1.2.1 Mine Experiment Results

The open field test can reflect the rat's activity and curiosity about the new environment. Horizontal movement reflects the rat's activity level, and the time spent in the central area and the number of standing times reflect the rat's curiosity and desire for the new external environment.

Table 1 Comparison of movement distance and central area residence time in open field test among rats in each group

Note: a: compared with the control group, P < 0.05; b: compared with the model group, P < 0.05

Table 2 Comparison of the number of open field standing times of rats in each group

Note: a: compared with the control group, P < 0.05; b: compared with the model group, P < 0.05

As shown in Tables 1 and 2, after chronic stimulation, the horizontal movement of the CUMS groups was lower than that of the control group; the central area residence time was higher than that of the control group, and the number of standing times was significantly reduced (P<0.05), indicating that the activity and curiosity of the rats were reduced after chronic stimulation.

After intervention, compared with the model group, the horizontal movement distance of rats in the Lactobacillus paracasei 207-27 group, the positive drug 1-MT group, and the positive drug fluoxetine group increased significantly, the central area residence time decreased significantly, and the number of standing times increased significantly (P<0.05). The horizontal movement distance of rats in the Lactobacillus paracasei 207-27 group was significantly greater than that of the two positive drug groups, and the central area residence time was lower than that of the two positive drug groups. Compared with the model group, the movement level of rats in the Lactobacillus paracasei 207-28, Lactobacillus paracasei 207-30, and Lactobacillus paracasei 207-31 groups did not change significantly. The results show that Lactobacillus paracasei 207-27, 1-MT, and fluoxetine intervention can improve the motor ability and exploration ability of CUMS rats in the open field test, enhance the curiosity of the external environment, and improve depression and anxiety behaviors. The Lactobacillus paracasei 207-27 strain has a better effect on improving the anxiety and depression behaviors of rats than positive drugs, and Lactobacillus paracasei has strain specificity in exerting this function.

1.2.2 Results of the elevated plus maze test and sugar water preference test

Table 3 Comparison of movement distance and sugar water preference of rats in each group in elevated plus maze test

Note: a: compared with the control group, P < 0.05; b: compared with the model group, P < 0.05;

As shown in Table 3, after chronic stimulation with CUMS, the horizontal movement and sucrose consumption were lower than those in the control group (P<0.05), indicating that the activity of rats decreased after chronic stimulation. After intervention, compared with the model group, the horizontal movement distance and sucrose consumption of rats in the Lactobacillus paracasei 207-27 group, the positive drug 1-MT group, and the positive drug fluoxetine group increased significantly (P<0.05), and the horizontal movement distance of rats in the Lactobacillus paracasei 207-27 group was significantly greater than that in the two positive drug groups; compared with the model group, the movement level of rats in the Lactobacillus paracasei 207-28, Lactobacillus paracasei 207-30, and Lactobacillus paracasei 207-31 groups did not change significantly. The results show that intervention with Lactobacillus paracasei 207-27, positive drug 1-MT and positive drug fluoxetine can increase the movement distance of CUMS rats in the elevated plus maze test, enhance the curiosity about the external environment, and improve depression and anxiety behaviors. Moreover, the Lactobacillus paracasei 207-27 strain has a better effect on improving the anxiety and depression behaviors of rats than positive drugs, and Lactobacillus paracasei has strain specificity in exerting this function.

1.2.3 Biochemical index results

The causes and mechanisms of depression are complex, mainly including the neurotransmitter hypothesis, the neuroendocrine hypothesis, immune response and neuroinflammation, and changes in intestinal flora. Current evidence shows that specific probiotic strains may reduce depressive symptoms and anxiety through one or more possible mechanisms, including affecting the synthesis of neurotransmitters such as 5-HT and GABA; regulating inflammation-related proteins and cytokines; or enhancing stress response by affecting stress hormones and the hypothalamic-pituitary-adrenal axis (HPA axis). The HPA axis is an important part of the neuroendocrine system, and the important hormone among them is cortisol (CORT), which is involved in the regulation of stress response.

Intestinal microbiota can also affect tryptophan metabolism, enteric nervous system, vagus nerve and immune system by regulating certain metabolites, communicate with the brain, and affect the occurrence and development of neuropsychiatric diseases. According to the previous behavioral results, this example measured the contents of 5-HT, DA, NE, GABA, GLU and CORT in the serum of mice in the blank group, model group, Lactobacillus paracasei 207-27 group and positive drug group.

Table 4 Comparison of 5-HT levels in serum and brain tissue of rats in each group

Note: a: compared with the control group, P < 0.05; b: compared with the model group, P < 0.05;

Table 5 Comparison of DA content in serum and brain tissue of rats in each group

Note: a: compared with the control group, P < 0.05; b: compared with the model group, P < 0.05;

Table 6 Comparison of NE content in serum and brain tissue of rats in each group

Note: a: compared with Control, P < 0.05; b: compared with CUMS, P < 0.05

Table 7 Comparison of GLU and GABA contents in brain tissue of rats in each group

Note: a: compared with Control, P < 0.05; b: compared with CUMS, P < 0.05

Table 8 Comparison of serum CORT levels in rats in each group

Note: a: compared with Control, P < 0.05; b: compared with CUMS, P < 0.05;

As shown in Tables 4 and 5, after chronic stimulation of CUMS, the contents of 5-HT and DA in serum and brain tissue were significantly reduced, and the difference was statistically significant (P<0.05), indicating that the depression and anxiety symptoms caused by CUMS stimulation can reduce the levels of 5-HT, DA, NE, GABA and GLU in rats and increase the CORT level. After intervention, compared with the model group, the contents of 5-HT, DA, NE, GABA and GLU in serum and brain tissue of rats in the Lactobacillus paracasei 207-27 group, the positive drug 1-MT group, and the positive drug fluoxetine group were significantly increased (P<0.05), and the CORT level was significantly reduced (P<0.05). This shows that Lactobacillus paracasei 207-27 can increase the levels of 5-HT, DA, NE, GABA and GLU in CUMS rats and reduce the CORT level, which is similar to the effects of positive drugs 1-MT and fluoxetine, and has the effect of regulating negative emotions such as depression and anxiety in rats.

Example 2. Study on the effect of Lactobacillus paracasei 207-27 on improving sleep quality in healthy adults

2.1 Study design

This study recruited 70 subjects (10 were excluded) for a 28-day randomized double-blind trial. The subjects were divided into a probiotic group and a placebo group, with 30 people in each group. They filled out sleep questionnaires before and after the trial and used sports bracelets to record their nighttime sleep data.

The inclusion criteria for the subjects were: 1. Aged 18-35 years old; felt stressed and had poor sleep quality; 2. Willing to take probiotics throughout the whole process, and cooperate with the correct use of the bracelet and filling out the questionnaire.

The exclusion criteria for subjects are as follows: 1. Those who have recently taken antibiotics, probiotics, prebiotics, etc. that may affect the test results (yogurt is not included); 2. Those with organic diseases, such as heart disease, liver cirrhosis, etc.; 3. Those with mental disorders; 4. Those diagnosed with chronic non-communicable diseases such as hypertension, gout, diabetes, etc. by hospitals at or above the county level; 5. Patients diagnosed with allergic diseases such as drug allergy, food allergy, rhinitis, etc. by hospitals at or above the county level, or those with a history of allergic diseases; 6. Those with a history of gastrointestinal surgery.

Most of the recruited subjects were students, and the study was conducted before the final exam. Therefore, these subjects reported that they were under great mental stress and had poor sleep quality. On this basis, the deep sleep duration of the subjects shown in Table 9 was sorted out according to the data from the sports bracelets worn by the subjects. In addition, the sleep scores shown in Table 9 were sorted out according to the sleep questionnaire scores filled out by the subjects, among which the sleep questionnaire scoring standards are: 0-5 points: very good sleep quality; 6-10 points: ok sleep quality; 11-15 points: average sleep quality; 16-21 points: very poor sleep quality.

2.2 Research Results

Table 9 Sleep results of subjects in the probiotic group and the placebo group

According to the subjects' sleep questionnaire scores and bracelet recording results, it can be concluded that after 28 days of probiotic intervention, the above two results were significantly improved. The subjects' sleep scores were significantly reduced (increased by 25%), the deep sleep time was significantly increased (increased by 36%), and the sleep quality was effectively improved.

The sleep quality of the subjects in the placebo group did not change significantly, and the deep sleep time was significantly reduced. The reason for the reduction may be that as time goes by, the test time is getting closer and closer, which leads to an increase in the anxiety level of the subjects. Therefore, the deep sleep time of the subjects who have not been intervened by probiotics has decreased after 28 days of testing, which also highlights the regulatory effect of Lactobacillus paracasei 207-27 of the present application on the sleep of the subjects.

In conclusion, Lactobacillus paracasei 207-27 can effectively improve the sleep quality of these healthy subjects.

Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and changes may be made to the details according to all the teachings that have been published, and these changes are within the scope of protection of the present invention. The entire invention is given by the attached claims and any equivalents thereof.

Claims (10)

1. Use of Lacticaseibacillus paracasei or its progeny, or a composition comprising said Lacticaseibacillus paracasei or its progeny in the preparation of a medicament or food, wherein said medicament or food is used for preventing and/or treating mood disorders in a subject, or preventing and/or treating diseases or symptoms caused by mood disorders; The Lactobacillus paracasei is deposited in Guangdong Microbiological Culture Collection Center with the deposit number of GDMCC No.60960. 2. The use according to claim 1, which has one or more characteristics selected from the following: (1) The mood disorders include depression and anxiety; (2) diseases and/or symptoms caused by mood disorders (e.g., depression) selected from the group consisting of depression, bipolar disorder, seasonal affective disorder, dysthymia, depressive personality disorder, altered mental status, or any combination thereof; Preferably, the depression is selected from: major depressive disorder, atypical depression, typical or melancholic depression, psychotic depression, catatonic depression, antenatal and/or postnatal depression, double depression, recurrent brief depression, minor depression, or any combination thereof; (3) Diseases and/or symptoms caused by mood disorders (e.g., anxiety) selected from panic attacks, panic disorder, agoraphobia, social phobia or social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (ASD), generalized anxiety disorder, acute stress disorder, or any combination thereof. 3. The use of claim 1 or 2, wherein the symptoms caused and/or resulting from the mood disorder include: sleep disorders (e.g., sleep apnea, narcolepsy, insomnia, parasomnias, sleep deprivation), feeling sad or depressed, confusion or decreased concentration, memory loss, excessive fear or worry, extreme guilt, extreme changes in mood swings, withdrawal from friends and activities, detachment from reality, paranoia or hallucinations, inability to cope with daily problems, stress, difficulty understanding situations and people, difficulty connecting with situations and people, significant changes in eating habits, changes in sexual desire, excessive anger, hostility or violence, suicidal thoughts, or any combination thereof. 4. The method of any one of claims 1 to 3, wherein the Lactobacillus paracasei or its progeny contained in the medicine or composition prevents and/or treats a mood disorder in a subject by affecting a stress response in the subject (e.g., increasing the level of serotonin (5-HT), dopamine (DA), norepinephrine (NE), gamma-aminobutyric acid (GABA) and/or glutamate (Glu), and/or reducing the level of cortisol (CORT)). 5. The use according to any one of claims 1 to 4, wherein the medicament further comprises another active ingredient; Preferably, the additional active ingredient is an additional drug; preferably, the additional drug is selected from anxiolytics, sedatives, hypnotics, antipsychotics, antidepressants, anticonvulsants, opioid analgesics, or any combination thereof; Preferably, the additional active ingredient is a dietary supplement; preferably, the dietary supplement is selected from melatonin, omega-3 dietary supplements, or any combination thereof. 6. The use according to any one of claims 1 to 5, wherein the medicine or food has one or more characteristics selected from the following: (1) The drug is a drug that is targeted for gastrointestinal release or a drug that is controlled for release in the gastrointestinal tract; (2) The drug further comprises a pharmaceutically acceptable carrier; (3) The drug is in the form of pills, powders, capsules, tablets (e.g., effervescent tablets), film-coated tablets, orally disintegrating granules, liquids, suppositories, or enemas; (4) the drug is administered to the subject orally, sublingually, nasally, intrathecally, bronchially, rectally, transdermally, by inhalation or parenterally; (5) The food is a dietary supplement or a health food; (6) The food further comprises prebiotics; Preferably, the prebiotic is selected from fructooligosaccharides, galacto-oligosaccharides, xylo-oligosaccharides, isomaltooligosaccharides, soybean oligosaccharides, inulin, spirulina, arthrospira, versicolor polysaccharide, carrot nitrogen-containing polysaccharide, casein hydrolyzate, α-lactalbumin, lactoferrin, or any combination thereof; (7) The food is selected from solid beverages, candies or juices, or the food is a dairy product (e.g., yogurt, flavored fermented milk, lactic acid bacteria beverage, cheese); (8) The food is in the form of pills, powders, capsules, tablets (e.g., effervescent tablets), orally disintegrating granules, or liquids. 7. The use according to any one of claims 1 to 6, which has one or more characteristics selected from the following: (1) The subject is a mammal; preferably, the mammal is selected from mice, pigs, rabbits, monkeys, sheep, and humans; (2) The Lactobacillus paracasei is administered to the subject in an amount of 10 ⁶ to 10 ¹² CFU/day dose. (3) The Lactobacillus paracasei is administered to the subject in an amount of 10 ⁶ CFU/daily dose, 10 ⁷ CFU/daily dose, 10 ⁸ CFU/daily dose, 10 ⁹ CFU/daily dose, 10 ¹⁰ CFU/daily dose, 10 ¹¹ CFU/daily dose, or 10 ¹² CFU/daily dose. 8. The use of any one of claims 1 to 7, wherein the composition comprises the Lactobacillus paracasei or its progeny, and additional bacteria and/or fungi (e.g. yeast), wherein the additional bacteria and/or fungi are probiotics or are edible. 9. The use according to claim 8, which has one or more characteristics selected from the following: (1) The probiotic bacteria are selected from the group consisting of Bifidobacterium, Lactobacillus, Lactobacillus casei, Lactobacillus mucosus, Lactobacillus plantarum, Lactobacillus univus, Lactobacillus spp., Streptococcus, Lactococcus, Propionibacterium, Propionibacterium, Leuconostoc, Pediococcus, Weizmannella, Zoococcus, Staphylococcus, or any combination thereof; (2) The yeast is of the genus Kluyveromyces; (3) The composition further comprises additional additives; Preferably, the additional additive is a nutrient selected from dietary fiber, prebiotics, protein, lipids, minerals, vitamins, plant extracts, or any combination thereof. 10. The use according to claim 9, wherein the use has one or more characteristics selected from the following: (1) The Bifidobacterium is selected from the group consisting of Bifidobacterium adolescentis, Bifidobacterium animalis subsp. animalis, Bifidobacterium animalis subsp. lactis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, Bifidobacterium longum subsp. longum, or any combination thereof; (2) the Lactobacillus is selected from the group consisting of Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacilus kefiranofaciens subsp. Kefiranofaciens, or any combination thereof; (3) the Lactobacillus species is selected from the group consisting of Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, or any combination thereof; (4) the Lactobacillus species is selected from the group consisting of: Limosilactobacillus fermentum, Limosilactobacillus reuteri, or a combination thereof; (5) The Lactobacillus species is Lactobacillus plantarum; (6) The Lactobacillus species is Ligilactobacillus salivarius; (7) The Streptococcus is Streptococcus salivarius subsp. thermophilus; (8) The Propionibacterium is Propionibacterium freudenreichiisubsp. shermanii; (9) The propionic acid bacteria is Propionibacterium acidipropionici; (10) The Lactococcus is selected from the group consisting of Lactococcus lactis subsp. Lactis, Lactococcus lactis subsp. Lactis biovardiacetylactis, Lactococcus cermoris, or any combination thereof.